Transgenic mice that overexpress the human trefoil peptide pS2 have an increased resistance to intestinal damage.

Marchbank, Tania; Goodlad, R A; Chinery, Rebecca; Poulsom, Richard; Hanby, Andrew M.

doi:10.1073/pnas.93.5.2137

Cited by 167 publications

(130 citation statements)

References 23 publications

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“…pS2 is generally expressed by mucus-producing epithelial cells, especially in areas of epithelial cell injury [22], and this could account for the expression of pS2 by epithelial cells in MSG biopsies. Furthermore, pS2, an oestrogen-induced regenerative protein, implicates the involvement of oestrogens which are well known inhibitors of apoptosis [23] in the defensive repertoire of epithelial cells in SS.…”

Section: Discussionmentioning

confidence: 98%

Modes of epithelial cell death and repair in Sjögren's syndrome (SS)

Polihronis¹,

Tapinos²,

Theocharis

et al. 1998

Clinical and Experimental Immunology

116

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SUMMARYWe evaluated possible modes of epithelial cell destruction and restoration in minor salivary gland biopsies from patients with SS. Minor salivary gland biopsies from 10 primary Sjögren's syndrome (pSS) patients and eight control individuals were evaluated by immunohistochemical staining for the expression of apoptosis-related molecules, substances released by activated cytotoxic T cells, as well as proteins involved in epithelial cell repair. The results were analysed by computer screen analysis and they were expressed as average percentages. Apoptosis-promoting molecules, Fas antigen and Fas ligand were observed in ductal and acinar epithelial cells as well as in infiltrating mononuclear cells of minor salivary glands from SS patients in comparison with control biopsies. Bax protein, which acts as a death-promoter message, was expressed in the ductal and acinar epithelial cells and in mononuclear infiltrating cells of SS patients compared with control individuals, while Bcl-2, an inhibitor of apoptosis, was primarily found in the lymphocytic infiltrates. In situ DNA fragmentation assay (TUNEL) revealed that epithelial cells were apoptotic in patients with SS compared with control subjects. Immunohistochemical staining for perforin and granzyme B, released from granules of activated cytotoxic lymphocytes, revealed their presence in lymphocytic infiltrates of patients with SS compared with control biopsies. pS2, a member of the trefoil protein family which functions as promoter of epithelial cell repair and cell proliferation, was expressed in epithelial cells in biopsies from SS patients. These studies suggest that the functional epithelium of minor salivary glands in patients with SS appears to be influenced by both intrinsic and extrinsic mechanisms of destruction, while a defensive mechanism of epithelial restoration seems to be active.

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Section: Discussionmentioning

confidence: 98%

Modes of epithelial cell death and repair in Sjögren's syndrome (SS)

Polihronis¹,

Tapinos²,

Theocharis

et al. 1998

Clinical and Experimental Immunology

116

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“…Interestingly, several in vitro and in vivo studies have demonstrated that trefoil peptides can also protect the intestinal epithelium from a variety of noxious agents, including bacterial toxins, chemicals, and drugs (10,(37)(38)(39)(40). It is unknown whether ITF could act to exert cytoprotective effects on the gastric epithelium integrity.…”

Section: Discussionmentioning

confidence: 99%

Intestinal trefoil factor activates the PI3K/Akt signaling pathway to protect gastric mucosal epithelium from damage

Sun

Yang

et al. 2014

International Journal of Oncology

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Abstract.Intestinal trefoil factor (ITF, also named as trefoil factor 3, TFF3) is a member of the TFF-domain peptide family, which plays an essential role in the regulation of cell survival, cell migration and maintains mucosal epithelial integrity in the gastrointestinal tract. However, the underlying mechanisms and associated molecules remain unclear. The aim of this study was to explore the protective effects of ITF on gastric mucosal epithelium injury and its possible molecular mechanisms of action. In the present study, we show that ITF was able to promote the proliferation and migration of GES-1 cells via a mechanism that involves the PI3K/Akt signaling pathway. Western blot results indicated that ITF induced a dose-and time-dependent increase in the Akt signaling pathway. ITF also plays an essential role in the restitution of GES-1 cell damage induced by lipopolysaccharide (LPS). LPS induced the apoptosis of GES-1 cells, decreased cell viability significantly (P<0.01) and led to epithelial tight junction damage, which is attenuated via ITF treatment. The protective effect of ITF on the integrity of GES-1 was abrogated by inhibition of the PI3K/Akt pathway. Taken together, our results demonstrate that ITF promotes the proliferation and migration of gastric mucosal epithelial cells and preserves gastric mucosal epithelial integrity after damage is mediated by activation of the PI3K/Akt signaling pathway. This study suggested that the PI3K/Akt pathway could act as a key intracellular pathway in the gastric mucosal epithelium that may serve as a therapeutic target to preserve epithelial integrity during injury.

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“…In addition to these gastrointestinal tract-specific promoters, fatty acid binding protein promoter is known to lead to expression of the DT-A gene within the small intestine (10,11). However, none of these promoters causes expression in goblet cells.…”

Section: Introductionmentioning

confidence: 99%

A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells

Itoh¹,

Beck²,

Inoue³

et al. 1999

J. Clin. Invest.

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MethodsPreparation of mITF promoter. To obtain a sufficiently large segment of 5′ flanking promoter region to confer goblet cell-specific expression of the transgene, a Hiroshi Itoh and Paul L. Beck contributed equally to this work.Received for publication January 5, 1999, and accepted in revised form October 21, 1999.Goblet cells are the major mucus-producing cells of the intestine and are presumed to play an important role in mucosal protection. However, their functional role has not been directly assessed in vivo.In initial studies, a 5′ flanking sequence of the murine intestinal trefoil factor (ITF) gene was found to confer goblet cell-specific expression of a transgene. To assess the role of goblet cells in the intestine, we generated transgenic mice in which ∼60% of goblet cells were ablated by the expression of an attenuated diphtheria toxin (DT) gene driven by the ITF promoter; other cell lineages were unaffected. We administered 2 exogenous agents, dextran sodium sulfate (DSS) and acetic acid, to assess the susceptibility of mITF/DT-A transgenic mice to colonic injury. After oral administration of DSS, 55% of control mice died, whereas DT transgenic mice retained their body weight and less than 5% died. Similarly, 30% of the wild-type mice died after mucosal administration of acetic acid, compared with 3.2% of the transgenic mice. Despite the reduction in goblet-cell number, the total amount of ITF was increased in the mITF/DT-A transgenic mice, indicating inducible compensatory mechanisms. These results suggest that goblet cells contribute to mucosal protection and repair predominantly through production of trefoil peptides. Construction of transgene and generation of β-galactosidase ITF transgenic mice. The β-galactosidase gene was obtained from pSV-β-galactosidase vector (Promega Corp., Madison, Wisconsin, USA) by digestion with BamHI and HindIII. The resulting 3.7 kb of β-galactosidase gene was inserted into the BamHI and HindIII sites of pBluescript II KS(+). The 6.3 kb of XhoI-digested 5′ end of the mITF promoter was then inserted into XhoI sites of pBluescript II KS(+) containing the β-galactosidase gene. The resulting plasmid was digested with BamHI, yielding a 10-kb DNA fragment consisting of the 6.35-kb mITF promoter followed by the β-galactosidase gene (3.7 kb). This fragment was gel purified, dialyzed, and injected into the mouse oocytes. The resulting offspring were screened both by Southern blotting (using the above β-galactosidase fragment as a probe) and by PCR using the following primers directed at the inserted β-galactosidase gene: sense: 5′-CCTGAGGCCGATACTGTCGTC-3′; antisense: 5′-CCAGATAACTGCCGTCACTCC-3′. PCR was performed according to the manufacturer's guidelines (Promega Corp.) using 0.5 µL of Taq DNA polymerase (Promega Corp.) in a 50-µL reaction containing 1.5 mM MgCl 2 , 0.2 mM dNTP, 0.8 µM of each primer, and approximately 1 µg of extracted tail DNA. PCR conditions included an initial 10 minutes at 95°C followed by 36 cycles each of 95°C for 1 minute, 58°C for 1 minute, 72°C f...

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Transgenic mice that overexpress the human trefoil peptide pS2 have an increased resistance to intestinal damage.

Cited by 167 publications

References 23 publications

Modes of epithelial cell death and repair in Sjögren's syndrome (SS)

Modes of epithelial cell death and repair in Sjögren's syndrome (SS)

Intestinal trefoil factor activates the PI3K/Akt signaling pathway to protect gastric mucosal epithelium from damage

A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells

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